The WHO estimates that almost 500 million people world-wide are chronically infected with HBV, HCV or HIV. China and Europe share a similar burden of infection with HIV and HCV but despite prophylactic vaccination, HBV continues to be a major health problem in China. The three viruses are transmitted similarly (blood products and sexual transmission), and vaccination against HIV and HCV has not been possible until now. A complicating problem for patients is that co-infections with two or even three different viruses have become a more frequent phenomenon. Interestingly, there are substantial differences in the rate of viral persistence after infection with the three viruses. Whereas it is virtually 100% for HIV, it is up to 80% for HCV, and less than 10% for HBV.
Thus, there are obvious differences in the mechanisms that lead to the establishment of chronicity by these viruses. One aim of the Transregio is to compare these differences in animal models and infected patients, as it might give new clues on how viral chronicity might be prevented. All viruses have to evade the innate and the adaptive immune system to become chronic. Hence, within the scientific Transregio network, these mechanisms will be intensively studied in cell culture, animal models, and patients.
It is generally accepted that once persistent infection is established some common features of the interaction of different viruses with the immune system apply. Theses common mechanisms, e.g. T cell exhaustion, mutational escape, regulatory T cell suppression, will also be a main area of research of the Transregio projects.
One other common factor is that all three chronic infections are difficult to treat. Current options for therapy are interferon alpha (HCV and HBV) and specific inhibitors of viral enzymes. However, these treatments are far from being optimal because of high therapy costs, severe side effects, and increasing problems with drug resistance mutations. Therefore, there is still an urgent need to better define the mechanisms of establishment of viral chronicity in HIV, HBV and HCV infection and to use this knowledge for developing new therapeutic strategies.
The most efficient means to prevent acute and subsequent chronic infection would be a safe and effective vaccine. Unfortunately, a prophylactic vaccine has only been established for HBV but after many years of research no vaccines against HCV or HIV exist. Thus, more basic research for the development of an HCV and HIV vaccine, which is part of the Transregio programme, should be performed.
For defining new strategies in vaccine development, it will also be important to better understand the factors that play a role in the transition from acute to persistent viral infections. Most of these factors should be related to the immune system of the infected host. Cells and molecules of the innate and adaptive immune system are able to fight most viruses and thus prevent severe acute diseases or chronic infection. This is orchestrated by semi-specific as well as highly specific recognition of the pathogen followed by an efficient elimination of free virus or virus-infected cells. The cell types and molecules involved in this process, demonstrating the importance of the system for the survival of the host are numerous. However, viruses that establish chronic infections have developed several different mechanisms to inhibit anti-viral functions of immune cells or their anti-viral molecules. As a result, viral replication can no longer be controlled and persistent infection is established. In the Transregio we are defining basic mechanisms of viral immunity and immune escape by viruses. The objective is to gain a fundamental understanding of the mutual interaction of chronic viruses with cells of the immune system and then to use this knowledge for developing new strategies of immunotherapy and vaccination.
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